Mo1037 Dysregulated Methionine Metabolism and Hyperhomocysteinemia in Diet-Induced Nonalcoholic Fatty Liver Disease

Purpose) The inflammasomes trigger the biological maturation of proinflammatory cytokines such as interleukin-1 beta or interleukin 18.They induce inflammation as expected, and also, they mediate host defence against microbial pathogens.Three Nod-like receptors (NLR family; NLRP1, NLRP3, NLRC4) are involved in the assembly of multiprotein complex inflammasomes.Recent advances in understanding pathological organ network such as intestine-to-liver revealed that intestinal inflammasomes have important role in the liver inflammation and fibrosis.It has been reported that intesitinal inflammasome activation plays an important role in the progression of NASH (Nature.2012).The intestinal inflammasome activation induces recovery of NASH and the somatic deletion of inflammasome gene results in progression of NASH.Anti-oxidants, such as vitamin E and pioglitazone have favorable effects in NASH.L-Carnitine plays an important role in mitochondrial beta-oxidation and has been reported to be effective in NASH.In this study, we examined the effects of vitamin E and L-carnitine as antioxidant supplementations on liver pathology and regulation of intestinal inflammasome activation in NASH mouse model.. (Methods) We used streptozotocin(STZ)-treated mouse diabetes model with high fat diet supplementation, known as the NASH hepatocarcinogenesis model (STAM mice).Eight-week-old STAM mice were divided into 3 experimental groups and fed for 4 weeks as follows:(1) high fat diet (S group) (2) high fat diet + L-Carnitine (SC group) (3) high fat diet + vitamin E (SE group).After 4 weeks mice were sacrificed.Following data were compared between these three groups; hepatic histological findings, hepatic 8-OHdG concentration, expression of hepatic inflammatory and hepatic lipogenic genes, and intestinal inflammasome related genes by real time PCR.(Results) In histological analysis, SC group and SE group showed low inflammation and fibrosis compared with S group.The concentration of 8-OHdG was reduced in SC and SE group compared with S group.The hepatic gene expression of inflammatory cytokine TNF-α was down-regulated in SC and SE group.The beta oxidation pathway related genes AOX and MCAD, the peroxisomal proliferator-activated receptor PPAR-α and PPAR-γ were up-regulated in SC and SE group.On the other hand, the intestinal inflammasome related genes were up-regulated in SC and SE group compared with S group.(Conclusion) Vitamin E and L-carnitine may prevent progression of non-alcoholic steatohepatitis with up-regulation of intestinal inflammasome activation.